ReviewBiology and pathobiology of lipid droplets and their potential role in the protection of the organ of Corti
Introduction
The observation of intracellular lipids is old in the field of cell biology. However, the study of the organelle chiefly involved in its storage, known as lipid droplet (LD), has just recently gained significant attention by basic scientists, clinical investigators, practitioners from many medical disciplines, and pharmaceutical companies. Fundamental studies in the field of cell biology, biophysics, and biochemistry, in particular those performed during the last twenty-five years, have revealed that LDs are not only involved in the storage but also in the release and metabolic processing of lipids and proteins involved in a number of intra-cellular and multi-cellular mechanisms. This field of research has been galvanized by extensive biochemical investigations that revealed that LDs are not simple inclusions of fat, but they have a constitutive cohort of resident molecules, including simple and complex lipids, steroids, and proteins, involved in a variety of critical cellular functions (Brown, 2001, Cermelli et al., 2006, Martin and Parton, 2006). In fact, a large number of laboratories around the world are currently working on extending these fundamental observations. The conceptual framework emerging from these studies is that, at a subcellular level, some components are involved in the regulation of the structure and function of the LD itself while others perform functions integrated at either the cellular or the whole organism level. Another focus of intensive investigation seeks to test the hypothesis that the molecular composition of LDs varies among cells, and even inside a single cell, according to their contributions to the structure and function of the resident tissue. This line of investigation is providing clues to the type and complexity of the contributions of LDs to cell specialization.
The study of LDs is pushing the development of technology ahead. This is evident by the increase in the application of very sophisticated biochemical and biophysical methods as well as genetically engineered model organisms. The most transformational impetus for the advancement of this field, however, can be found in the current need of translating the knowledge from the laboratory to the clinic at a faster pace. For instance, one of the most rapidly growing cause for disease in USA, and in many places around the world, are those associated with fat accumulation, storage, metabolism, and its conversion to energy. At the organelle level, the management of fat begins with the function of the LDs in adipocytes. The obesity epidemic has endowed us with bodies that carry and recycle a large amount of fat, which in many cases has direct toxic effects. For instance, the accumulation of fat in LDs underlies the pathogenesis of NASH (Non-Alcoholic SteatoHepatitis), a liver disease which has become one of them most frequent cause of death in modern medical practice (Karagozian et al., 2014). It appears, that unbalanced lipid management by cells, leads to “lipoapoptosis”, with concomitant inflammation, fibrosis, and organ failure, a process further enhanced by various toxins, including some commonly used drugs (Anderson and Borlak, 2008).
A nascent but very promising area of investigation involves studies on the function and disfunction of LDs in other organs and cell populations, besides the liver and adipocytes. This research is guided by the hypothesis that LDs would play a role in the biology and pathobiology of every organ and cell population just like in liver and adipocytes. It is on this shore of the current research tide that our laboratory is actively investigating the potential contribution of LDs to maintaining the health of the auditory organ. We want to understand how these organelles and their component mediate or antagonize the effects of ototoxic agents, as well as whether and how they participate in the development of human diseases. Therefore, in the current article we review the existing knowledge in this field, highlight the most current research directions, and describe a useful paradigm that can help in better understanding the role of LDs in the biology and pathobiology of auditory diseases.
Section snippets
Early functional paradigms for understanding the contribution of LDs to the function of the auditory organ
In most cells other than adipocytes, LDs are too small or too few to be seen in histological sections. Confocal and electron microscopy, however, revealed that LDs exist nearly ubiquitously from bacteria to mammals, and current theories coincide in that all mammalian cells contain LDs but their size and number is cell type- and species-dependent (Ohsaki et al., 2014). For example, LDs are a well-known feature of guinea pig Hensen cells ((Hallpike, 1936, Kimura, 1975, Vinnikov and Titova, 1964)
Lipid droplets: from static fatty inclusions to dynamic organelles
LDs are ubiquitous dynamic organelles that synthesize, store, and supply lipids in cells from diverse organisms, including bacteria, yeast, plants, insects and animals. While the earliest descriptions of this organelle date back to the 19th century (Altmann, 1890, Wilson, 1896), they were ignored for decades by cell biologists thereafter because of their perceived role as inert fat particles (Farese and Walther, 2009). In the early 1900s, LDs achieved recognition as organelles present in most
Biogenesis of lipid droplets
Biogenesis of LDs is a poorly understood process involving the formation of a monolayer-bound organelle from a bilayer membrane. Additionally, large LDs can form either by growth of existing LDs or by the combination of smaller LDs through several distinct mechanisms. The most accepted theory of the origin of LDs postulates that they are most likely generated at the ER membrane (Jacquier et al., 2013, Jacquier et al., 2011). LDs are often found in close proximity to the ER and, in some
Lipidomics of lipid droplets
All LDs functions are rooted in their unique architecture. In contrast to other organelles that have aqueous content within a phospholipid bilayer membrane, the LDs basic structure is a phospholipid monolayer (or hemi-membrane) surrounding a core of neutral lipids (Fig. 1). In mammalian LDs the phospholipid monolayer contains phosphatidylcholine (PC) and phosphatidyl ethanolamine (PE) as in other membranes, but it is peculiar in that also contains lyso-PC and lyso-PE with abundant unsaturated
Proteomics of lipid droplets
LDs contain numerous proteins at their surfaces, where they control lipid synthesis, initiate lipid droplet fusion and promote lipid hydrolysis. Interestingly, some studies showed presence of proteins, including soluble ones, in the LD core (Bozza et al., 1997, Dvorak et al., 1992, Robenek et al., 2005, Robenek et al., 2006) (Fig. 1), where they play still unknown functional roles. It is not plausible that hydrophilic proteins exist alone in the core, but amphiphilic proteins may complex with
Biophysics of lipid droplets
Although LDs emerging from the ER would be very small (Khandelia et al., 2010, Zanghellini et al., 2010), many cells possess large LDs. Moreover, LDs size varies not only between different cells but also inside a single cell and at different time-points, growing and shrinking in response to cellular signals. Although, from a biophysical point of view, LDs may be considered an emulsion (Thiam et al., 2013), the precise control of LDs size makes them different from a simple two-phase system. The
Lipid droplets and human diseases
The worldwide pandemic of obesity has serious health consequences, and constitutes serious challenges to both biomedical research and treatment (Popkin et al., 2012). It is widely accepted that we become overweight and even obese because our intake of energy (food) exceeds our caloric expenditure. Our bodies first adapt to this chronic state of increased energy supply by accessing the high capability of white adipose tissue to store surplus energy as neutral lipids in large, unilocular LDs.
LDs in the cochlea: part of an anti-inflammatory mechanism?
The cochlea was originally considered an immunologically privileged organ because it is separated from the systemic circulation by a blood-labyrinth barrier physiologically similar to the blood–brain barrier of the central nervous system. However, this postulate has been challenged by the observation that inflammatory responses in the cochlea occur in the presence of bacterial or viral pathogens, antigens that cause labyrinthitis, as well as noise- or drug-induced damage (Fujioka et al., 2014a,
Concluding remarks
While upon their discovery LDs were thought to be simply an inclusion body, today we know that they are ubiquitous and important organelles present in every cell from many organisms across evolutionary kingdoms. This exquisite conservation suggest that a strong evolutionary pressure must have been exerted on cells to careful and dynamically partition large concentrations of vital lipids within the cytoplasm. Most current theories infer that this evolutionary pressure relates to the
Acknowledgments
The authors thank Yi Guo, Yin Peng, Gwen Lomberk, Gilda Kalinec and Pru Thein for critically reading the manuscript. FK is supported by NIH Grants DC010146 and DC 010397 and UCLA's Department of Head and Neck Surgery funds; RU is funded by NIH grant DK52913, the Mayo Clinic Center for Cell Signaling (P30DK084567), SPORE P50 CA102701, and Mayo Foundation funds. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of these
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